Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that functions by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semisynthetic analogs have the following general structural formulae: ##STR2## wherein: Z is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sub.1 is: ##STR3## wherein Q is ##STR4## R.sub.3 is H or OH; and R.sub.2 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds. PA1 R.sup.2 and R.sup.6 are independently PA1 R.sup.3 and R.sup.4 are independently: PA1 R.sup.7 and R.sup.8 are independently: PA1 X and Y independently are hydrogen, halogen, trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or a group selected from: PA1 a, b and c each represent single bonds or one of a, b and c represents a double bond or both a and c represent double bonds; PA1 R.sup.1 and R.sup.5 are independently selected from: PA1 R.sup.1 and R.sup.5 are independently: PA1 (a) adding the substrate to a growing culture of Nocardia autotrophica for a suitable incubation period followed by isolation, and derivatization if desired; PA1 (b) collecting a culture of the bioconverting microorganism and contacting the collected cells with the substrate; or PA1 (c) preparing a cell-free, enzyme-containing extract from the cells of the bioconverting microorganism and contacting this extract with the substrate.
U.S. Pat. No. 4,517,373 discloses semisynthetic hydroxy containing compounds represented by the above general formula wherein R.sub.1 is ##STR5##
U.S. Pat. No. 4,517,859 and U.S. Pat. No. 4,448,979 also disclose semisynthetic hydroxy-containing compounds represented by the above general formula wherein R.sub.1 is ##STR6##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.S. Pat. No. 4,376,863 discloses a fermentation product, isolated after cultivation of a microorganism belonging to the genus Aspergillus, which has a hydroxy-containing butyryloxy side chain and is represented by the above general formula wherein R.sub.1 is ##STR7##
Japanese unexamined patent application No. J59-122,483-A discloses a semisynthetic hydroxy-containing compound represented by the above general formula wherein R.sub.1 is ##STR8##